ClinicalinvestigationsexaminingbiomarkercandidatesinGulfWarVeterans'Illnesses(GWVI)arelimited, andstudiesthatencompassbothbaselineand10?yearfollow?updataforbloodbiomarkercandidatesare currentlyunavailable.Wethusproposetoconducta10?yearfollow?upinvestigationinGulfWarVeterans toexaminepromisingbloodbiomarkercandidatesatbaselineand10?yearfollow?up,aprojectthathasthe potentialtoberapidlycatalyzedintoclinicallyefficaciousinterventionsforGWVI. Ourpreliminarybaselinedatainserumsamplescollected2005?2014fromVeteranswhoservedintheGulf Warera(1990?1991)suggestsignificantdifferencesinanumberofbiomarkercandidatesinVeteranswho hadbeendeployedtotheGulfWartheater(comparedtoVeteranswhohadservedinthe1990?1991Gulf Warera,butwhohadnotbeendeployedtotheregionofconflict).Baselinepilotstudiessuggestthat VeteranswithahistoryofdeploymenttotheGulfWartheaterdemonstrate:a.)alteredneurosteroid metabolism,possiblysecondarytoendocrinedisruptioninvolvingchemicalagentexposures(amongother potentialetiologies),b.)reductionsinVitaminD(implicatedinprocessesrelevanttoGWVI,including inflammation,cancer,andenvironmentalexposures,c.)elevationsinacylcarnitinesandotherendogenous esters(potentiallysignalingmitochondrialchanges),andd.)elevationsinc?reactiveprotein(amarkerof inflammationlikelyrelevanttoGWVI).Our recent data demonstrate that many of these analytes are also significantly associated with possible symptoms of GWVI,furtherstrengthening the rationale for this project. AllofthesebiomarkercandidateshavethepotentialtoberapidlytranslatedintonewtreatmentsforGWVI, consistentwithInstituteofMedicine's(IOM)recentrecommendationsthat?FutureGulfWarresearchshould placetoppriorityontheidentificationanddevelopmentofeffectivetherapeuticinterventionsandmanagement strategiesforGulfWarillness?(2016).Wethusproposetoexaminebiomarkercandidatesatbaselineandalso at10?yearfollow?upinVeteransofthe1990?1991GulfWareratoinformtherapeuticdevelopment. 1.Basedonstrongpilotdata,weproposetoconductbaselinebiomarkerinvestigationsin527GulfWarera Veteransforwhomserumsamplesarealreadycollected.Wehypothesizethatwewillreplicateourpilotfindings showingalterationsinneurosteroidmetabolism,VitaminD,acylcarnitines,andinflammatorymarkersinGulfWar VeteranswithahistoryofdeploymenttotheGulfWartheaterofoperations. 2.As94%ofthe527GulfWareraVeteranswhoprovidedabloodsamplebetween2005?2014have alreadyprovidedexplicitpermissiontobere?contactedforfutureresearchstudies(i.e.agreeingtothisin theconsentformoftheoriginal2005?2014study),andasourrecentfeasibilitystudyshowsthat75%of previouslyenrolledVeteranscanindeedbesuccessfullyre?contactedandarealsowillingtoparticipatein newresearchstudies,weproposetoconducta10?yearfollow?upstudy(+/?2years)in400GulfWar VeteranstodetermineifbiomarkerchangesinVeteranswithahistoryofdeploymentpersist10yearslater, andpotentiallypredictpain,cognitivesymptoms,generalmedicalhealth,andfunctionaloutcomes. 3.Exploratory:Ofthe527GulfWareraVeteransintheproposedcohort,approximately20%hadbaseline neuroimagingstudiesduringthe2005?2014interval(structuralMRI+/?DTI).Ourpreliminarydata suggestthatneurosteroidlevelsinbloodarerelevanttobrainstructureandfunction.Wethusproposeto conduct10?yearfollow?upMRIandDTIassessmentsin50GulfWarVeteransforwhombaseline neuroimagingstudiesconductedduringthe2005?2014intervalarecurrentlyavailable. ThesebiomarkerinvestigationscouldcontributetoidentifyingnewtreatmentinterventionsforGWVIthat aremechanisticallyanchoredandaddresspathophysiologicalalterationsrelevanttothecondition.They couldalsofunctionaspredictorsofGWVIsymptomsandtherapeuticresponse.